Multiple myeloma (MM) is the second most common hematological malignancy. MM remains incurable despite that various therapeutic agents, including proteasome inhibitors (e.g., bortezomib) and immunomodulatory drugs (e.g., thalidomide and lenalidomide), are available. A major challenge for molecular targeted therapy in MM is its genetic complexity and molecular heterogeneity. Gene transcription within the tumor cell and its microenvironment can also be altered by epigenetic modulation (e.g., acetylation and methylation). Thus, inhibition of histone deacetylases (HDACs) has emerged as a novel targeted treatment strategy in MM.
Historic deacetylases are divided into 4 classes: class-I (HDAC1, 2, 3, 8), class-IIa (HDAC4, 5, 7, 9), class-IIb (HDAC6,10), class-III (SIRT1-7), and class-IV (HDAC11). These classes differ in their subcellular localization (class-1 DACs are present in nucleus and class-II enzymes are cytoplasmic) and their intracellular targets. Although HDAC is based on histone target proteins, recent studies reveal at least 3,600 acetylation sites on 1,750 non histone proteins in cancer cells associated with various functions including gene expression, DNA replication and repair, cell cycle progression, cytoskeletal reorganization, and protein chaperone activity. Clinical trials with non-selective HDAC inhibitors (HDACi) have shown efficacy, but are limited due to side effects, such as fatigue, diarrhea, and thrombocytopenia.
Thus, there is currently a need to develop HDAC inhibitors to treat hematological cell proliferative disorders, such as MM, that have minimal adverse side effects. The present invention addresses the need.